MRI Studies of Brain Function and Metabolism ? Annual Report 2002 The functional MRI group of CBDB consists of multidisciplinary specialists with expertise in neurology, psychiatry, physics, biology and MRI techniques. This group pursues a variety of research agendas involving study of brain function and metabolism in normal healthy controls and patients with neuropsychiatric disorders. The lion's share of the effort of this group over the last couple of years has been in implementing Imaging Genomics, a new paradigm in brain research using clinical genetics and neuroimaging, to explore the basic molecular biology and genetics of human information processing in normal health and as related to major psychiatric illnesses. Several interesting findings have emerged from these studies: 1) In a study aimed at exploring the effects of functional polymorphisms of dopamine system related genes, we found that Val-Met polymorphism in the catechol-O-methyltransferase (COMT) gene [COMT is an enzyme in the catabolic pathway of dopamine] appears to predict the efficiency of prefrontal cortical (PFC) neuronal function as measured by BOLD fMRI during a working memory task. We found that there was an apparent allelic load effect; wherein the high enzyme activity val allele predicted the least efficient BOLD fMRI response in PFC, i.e. greater activation for the same level of task performance when compared to the met allele, and the presence of the low enzyme activity met allele conferred greater prefrontal cortical efficiency. These data emphasize the importance of optimal dopamine tone in prefrontal cortex for modulating working memory performance. Since the original observation, we have replicated this finding in two more cohorts. 2) In another study, we explored the effect of this COMT polymorphism on the neuromodulatory actions of amphetamine on PFC. Amphetamine enhanced the efficiency of PFC function in subjects with val-val genotype at all levels of task difficulty, whereas in subjects with met-met genotype the drug had a deleterious effect during the high load condition. These data are consistent with evidence in animals of an inverted U functional response curve to increasing dopamine signaling in PFC and suggest that individuals with the met158-met COMT genotype are at increased risk of an adverse response to clinical doses of amphetamine. 3) We also explored the effects of allelic variation in monoamine system genes on the response of brain regions implicated in emotion processing. A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin (5-HT) function influences both normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We found that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity in response to fearful stimuli in comparison to individuals homozygous for the long allele. These results are the first to demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele. In addition to the above studies, we also pursued studies with pharmacological manipulations to directly explore the effects of monoamines on brain function. Several interesting results have emerged from these studies as well. 1) In a study aimed at investigating the modulatory effects of dopaminergic therapy on neural systems subserving working memory and motor function we studied patients with Parkinsons disease in a relatively hypodopaminergic state and in a dopamine replete state. We found that in contrast to the cortical motor regions which showed greater activation during the dopamine replete state, the cortical regions subserving working memory showed greater extent of activation during the relatively hypodopaminergic state. These results are consistent with evidence that dopamine modulates the cortical networks subserving working memory and motor function via two distinct mechanisms ? nigrostriatal projections facilitate motor function indirectly via thalamic excitatory projections to motor cortices while the mesocortical dopaminergic system facilitates working memory function via direct inputs to prefrontal cortex. The results are also consistent with other evidence that the hypodopaminergic state is associated with decreased efficiency of prefrontal cortical information processing and that dopaminergic therapy improves physiological efficiency of this region. 2) Using a similar design we also explored the physiological effects of dopaminergic manipulation on the response of the amygdala during the perceptual processing of fearful stimuli. We found a robust bilateral amygdala response in normal controls that was absent in patients with Parkinsons disease during the hypodopaminergic state. Dopamine repletion partially restored this response in the patients. These results are consistent with findings in experimental animal paradigms and provide the first in vivo demonstration of the role of dopamine in modulating the response of the amygdala in human subjects. Further, they demonstrate for the first time an abnormal amygdala response in PD that may underlie the emotional deficits accompanying the disease. 3) Using a similar task, we also found that amphetamine potentiated the response of only the amygdala but not other regions. These results may provide insight to the underlying neural substrate of the anxiogenic effects of amphetamine. The group also pursued studies to explore the neurophysiological correlates of altered brain function associated with senescence. In a study aimed at exploring the neurophysiological correlates of reduced working memory capacity with age we found that the effect of aging on cortical function is complex. Within working memory capacity, compensatory mechanisms, such as increased activation and recruitment of new cortical regions, kick in to maintain proficiency. Beyond capacity, however, i.e. as cognitive load increases compensatory mechanisms are no longer engaged with a resultant decrement in performance. We also found that similar to the cognitive networks, the entire motor network also is functioning with decreased efficiency in the aging brain. These changes may reflect the reorganization and redistribution that takes place with aging in the functional networks to compensate for the age-related structural and neurochemical changes. Studies are being pursued to explore the effect of aging on other brain systems, and the role of genetics on these changes.